PTEN (phosphatase and tensin homolog) encodes a lipid phosphatase that negatively regulates the PI3K signaling pathway. Its primary role is to counteract PI3K kinase activity and thus inhibit the activation of AKT. PTEN, widely recognized as a tumor suppressor, has been extensively studied in tumor biology, as loss of PTEN function is the second most common type of mutation (next to P53) found in human cancers. New studies, however, show that PTEN also plays a role in neurological disorders, such as Parkinson Disease, epilepsy, and Autism Spectrum Disorders (ASD). The PTEN-regulated PI3K/AKT signal transduction pathway crosstalks with several other important signaling pathways, including Wnt/GSK3, which is linked to Schizophrenia (SZ) and bipolar disorder (BD). While these functional aspects of PTEN have been extensively studied in the context of its lipid phosphatase activity on PI3K, PTEN can also inhibit cell growth through its protein phosphatase activity. More recently, it was discovered that PTEN has a third function that is totally independent from its encoded protein; PTEN mRNA forms a competing interaction with other RNAs due to shared miRNA targets sites, with the most notable case being PTENP1, a pseudogene derived from PTEN. Motivated by this new intriguing finding and our long-standing interest in pseudogene function and the genetic basis of ASD/BD/SZ, we propose to investigate the role of this PTEN/PTENP1 interaction in early neurogenesis and to identify the miRNA regulatory network behind this interaction using a systems genomic approach and induced pluripotent stem cell (iPSC) technology for in vitro modeling of neurodevelopment. We hypothesize that mutations or polymorphisms affecting PTENP1 expression or interfering with the PTEN-miRNA-PTENP1 interaction will perturb this competing RNA network system and thus could represent new risk factors for ASD, SZ and other neurodevelopmental disorders. Our findings will be important for understanding the role of non-coding RNAs and pseudogenes in neuropsychiatric disorders, both of which may help explain disease-associated SNPs and CNVs in non-coding regions of the human genome. PUBLIC HEALTH RELEVANCE: This project will investigate the interacting roles of human gene PTEN and its deriving pseudogene PTENP1 in early neurogenesis and their implications in neurodevelopmental disorders using a systems genomics approach.